Volume 47, Issue 6, Pages 390-410 (December 2012) Electrical Status Epilepticus in Sleep: Clinical Presentation and Pathophysiology  Iván Sánchez Fernández, MD, Tobias Loddenkemper, MD, Jurriaan M. Peters, MD, Sanjeev V. Kothare, MD  Pediatric Neurology  Volume 47, Issue 6, Pages 390-410 (December 2012) DOI: 10.1016/j.pediatrneurol.2012.06.016 Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 1 Timeline of electroclinical syndromes in the spectrum of electrical status epilepticus in sleep, with approximate age of onset and remission/improvement in most patients. BECTS, benign childhood epilepsy with centrotemporal spikes; CSWS, continuous spikes and waves during sleep; LKS, Landau-Kleffner syndrome; LOCOE-G, late-onset childhood occipital epilepsy (Gastaut type); PS, Panayiotopoulos syndrome. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 2 Graphic representation of the evolution over time of continuous spikes and waves during sleep. The age at occurrence of the different clinical events varies in individual patients, but tends to peak at around the displayed ages. EEG, electroencephalogram; R, regression; SF, seizure freedom; SO, seizure onset; y, years. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 3 Electroencephalogram tracings in different moments of the sleep-wake cycle. Note that drowsiness (NREM1) and REM sleep can be difficult to differentiate. If NREM1 and REM sleep are mistaken for one another, the epileptiform activity in non-REM sleep could be either overestimated or underestimated. Chin electromyography (CHIN1-CHIN2 channel in this tracing) and an electrooculogram (LOC-ROC channel in this tracing) can facilitate the differentiation of those two patterns. Note the dramatic activation of epileptiform activity from wakefulness to non-REM sleep. The near-continuous spike-waves severely disrupt the electroencephalogram sleep tracing, making normal sleep patterns unrecognizable. In this setting, to differentiate NREM2 from NREM3 based only on the appearance of the electroencephalogram tracing is very difficult. Note different voltages in different tracings. NREM, nonrapid eye movement sleep; NREM1, NREM2, and NREM3, three stages of non-REM sleep; REM, rapid eye movement sleep; W, wakefulness. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 4 Different electroencephalogram expressions of electrical status epilepticus in sleep. Epileptiform activity appears much more frequently in A than in B. If the reader quantifies the epileptiform activity by counting the 1-second bins occupied by spike-waves, both tracings (A and B) express 100% of epileptiform activity (spike-waves are present in every 1-second bin). However, if the reader counts the total number of individual spikes per unit of time, epileptiform activity is almost double in A than in B. In A and B, spike-waves occupy more or less symmetrically both hemispheres, whereas in C, electrical status epilepticus in sleep is unilateral and occupies only the left hemisphere. Note different voltages in A, B, and C. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 5 Vascular lesions in patients with continuous spikes and waves during sleep. Three different patients (A, B, and C) manifested an early developmental vascular lesion affecting the left thalamus. In top row, magnetic resonance images are presented as T2-weighted images in coronal sequence. In lower row, magnetic resonance images are presented as T2 fluid attenuated inversion recovery-weighted images in axial sequence. Severe encephalomalacia in the distribution of the left middle cerebral artery affects the three patients with differing severity. Patients A, B, and C developed continuous spikes and waves during sleep during their childhood. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 6 Simplified schematic representation of the anatomic and functional interactions between GABAergic neurons in the reticular nucleus and glutamatergic thalamocortical neurons. Reticular neurons send inhibitory GABAergic projections to the thalamocortical neurons in the dorsal thalamic nuclei. Thalamocortical neurons send excitatory glutamatergic projections to the cerebral cortical neurons, and send back collaterals to the reticular neurons. Both reticular and thalamocortical neurons receive excitatory glutamatergic projections from the cerebral cortical neurons. The influence of cerebral cortical neurons on thalamocortical neurons is discrete, and is represented by the thinner line in that projection. CN, cortical neurons; RN, reticular neurons; TCN, thalamocortical neurons. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 7 Simplified schematic representation of the anatomic and functional interactions between the spindle rhythm generator, the cerebral cortex, and the reticular activating system. The glutamatergic projections from cerebral cortex neurons activate the spindle rhythm generator. The projections from the subcortical reticular activating system exert an inhibitory modulation effect on the spindle rhythm generator. CN, cortical neurons; RAS, reticular activating system; RN, reticular neurons; TCN, thalamocortical neurons. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 8 Simplified schematic representation of neighbor inhibition in the reticular nucleus. The activated reticular neurons inhibit neighboring reticular neurons through the release GABAA. This mechanism prevents hypersynchronization. RN, reticular neurons; TCN, thalamocortical neurons. Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions

Figure 9 Evolution of neurotransmitter receptors expression over time. During the critical period (shaded rectangle), excitatory receptors are overexpressed, and inhibitory receptors are underexpressed compared with any other period of life. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, gamma-aminobutyric acid; NMDA, N-methyl-d-aspartate. (Adapted with permission from Rakhade and Jensen [159], by permission of Macmillan Publishers, Ltd., ©2009.) Pediatric Neurology 2012 47, 390-410DOI: (10.1016/j.pediatrneurol.2012.06.016) Copyright © 2012 Elsevier Inc. Terms and Conditions